Chapter 18 The Cell-Division Cycle Essential Cell Biology FOURTH EDITION Copyright © Garland Science 2014 Alberts • Bray • Hopkin • Johnson • Lewis • Raff • Roberts • Walter
20 µm 100 µm 200 µm (a) Reproduction. An amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individual organism (LM). (b) Growth and development. This micrograph shows a sand dollar embryo shortly after the fertilized egg divided, forming two cells (LM). (c) Tissue renewal. These dividing bone marrow cells (arrow) will give rise to new blood cells (LM). The Functions of Cell Division Page 603
Cell Cycle: 1.M phase 2.Interphase Page 605
Page 604, 605 & 622
( nuclear division) (division of the cytoplasm) Page 604 & 605
Page 605 M phase is typically much shorter and G1 much longer than shown.
Page 604 & 605
Embryonic Cell Cycles Page 604 & 605
2n 4n
THE CELL-CYCLE CONTROL SYSTEM
THE CELL-CYCLE CONTROL SYSTEM The Cell-Cycle Control System Depends on Cyclically Activated Protein Kinases called Cdks Different Cyclin–Cdk Complexes Trigger Different Steps in the Cell Cycle Cyclin Concentrations are Regulated by Transcription and by Proteolysis The Activity of Cyclin–Cdk Complexes Depends on Phosphorylation and Dephosphorylation Cdk Activity Can be Blocked by Cdk Inhibitor Proteins The Cell-Cycle Control System Can Pause the Cycle in Various Ways
Control system G 2 checkpoint M checkpoint G 1 checkpoint G 1 S G 2 M Cell Cycle Control System Page 606
Page 606
Page 607 & 608 Kinase Cyclin Maturation-Promoting Factor (MPF) Mitosis-Promoting Factor(M-phase Promoting Factor) (cyclin-dependent kinase)
Figure 18–7 MPF activity was discovered by injecting Xenopus egg cytoplasm into Xenopus oocytes. (A) A Xenopus oocyte is injected with cytoplasm taken from a Xenopus egg in M phase. The cell extract drives the oocyte into M phase of the first meiotic division (a process called maturation), causing the large nucleus to break down and a spindle to form. (B) When the cytoplasm is instead taken from a cleaving egg in interphase, it does not cause the oocyte to enter M phase. Thus, the extract in (A) must contain some activity—a maturation promoting factor (MPF)—that triggers entry into M phase Page 610
Fluctuation of MPF Activity and Cyclin Concentration During the Cell Cycle Page 607 & 608
Cdk Cdk G 2 checkpoint Cyclin MPF Cyclin is degraded Degraded Cyclin G 1 G 2 S M Cyclin accumulation Fluctuation of MPF Activity and Cyclin Concentration During the Cell Cycle Page 607 & 608
( fission yeast) (D1,D2& D3) (E1& E2) (A1& A2) (Cdk1) (B1 & B2) Page 607 & 608
Page 608 & 611
Mechanisms of Cdk (cyclin-dependent kinase) Regulation
Mechanisms of Cdk (cyclin-dependent kinase) Regulation (Cyclin binding) (Cdk phosphorylation state) (Cdk phosphorylation state) 3 2’ (Cdk inhibitors) 4. Controlled proteolysis 5. Subcellular localization 167 Page 611-613
Cdc2=Cdk1 2.Cdk Phoshorylation State Page 612
RB Is a Major Substrate for Cdk-cyclin D Complexes Page 612,614 & 615
Page 614 & 615
The CKI Proteins Fall into Two Classes: 1.The Kip Family 2.The INK4 Family The Kip family The INK4 family 3. Cdk Inhibitors (CKIs) Page 612
Page 612
4. Controlled Proteolysis Page 611
Page 612
Cyclin B1 in G2 phase 5. Subcellular localization
Cyclin B1 in M phase
Page 613
G1 PHASE
G 1 PHASE Cdks are Stably Inactivated in G 1 Mitogens Promote the Production of the Cyclins that Stimulate Cell Division DNA Damage Can Temporarily Halt Progression Through G 1 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States
Page 613 & 614
G 1 checkpoint G 1 G 1 G 0 (a) If a cell receives a go-ahead signal at the G 1 checkpoint, the cell continues      on in the cell cycle. (b) If a cell does not receive a go-ahead signal at the G 1 checkpoint, the cell exits the cell cycle and goes into G 0 , a nondividing state. The G1 checkpoint (Restrction Point) Page 615 & 616 Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States
Mitogens Promote the Production of the Cyclins that Stimulate Cell Division Page 614
Page 614 One way in which mitogens stimulate cell proliferation is by inhibiting the Rb protein
DNA Damage Can Temporarily Halt Progression Through G1 Page 615 & 616
S PHASE
S PHASE S-Cdk Initiates DNA Replication and Blocks Re -Replication Incomplete Replication Can Arrest the Cell Cycle in G 2
Page 616 & 617
The molecular mechanisms governing the initiation of DNA replication *ORC(origin-recognition complex) *Cdc6 & Cdt1(replicator activator proteins) *MCM (replication licensing factor) Geminin Page 616 - 618
M PHASE
M PHASE M-Cdk Drives Entry Into M Phase and Mitosis Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis M Phase Occurs in Stages
M-Cdk Drives Entry Into M Phase and Mitosis Page 618 & 619
Cdc2=Cdk1
Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation Page 620
Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis Page 619 & 620
Page 628
Page 628
FIGURE 19-38 The Anaphase-Promoting Complex and the Mitotic Spindle Checkpoint. (a) The anaphase-promoting complex controls the final stages of mitosis by targeting selected proteins, including securin and mitotic cyclin, for destruction. (b) A model for the mitotic spindle checkpoint shows how chromosomes that are not attached to the spindle may organize Mad and Bub proteins into a complex that inhibits the anaphase- promoting complex, thereby delaying the onset of anaphase until all chromosomes are attached to the spindle.
Three Broad Categories of Cell: 1.Cell that are highly specialized and lack the ability to divide 2.Cells that normally do not divide but can be induced to begin DNA synthesis and divide when given an appropriate stimulus 3.Cells that normally possess a relatively high level of mitotic activity
Page 622
Page 622
Page 622
Page 622
Page 623 Metaphase is the longest stage of mitosis, lasting about 20 minutes.
Page 623 Anaphase is the shortest stage of mitosis, lasting only a few minutes
Page 623
Page 623
Page 625
Page 626
Page 626
Page 628
Page 628
Page 629 The Nuclear Envelope Re-forms at Telophase
Figure 18–32 The contractile ring divides the cell in two. Page 631
CONTROL OF CELL NUMBERS AND CELL SIZE
CONTROL OF CELL NUMBERS AND CELL SIZE Apoptosis Helps Regulate Animal Cell Numbers Apoptosis Is Mediated by an Intracellular Proteolytic Cascade The Intrinsic Apoptotic Death Program Is Regulated by the Bcl2 Family of Intracellular Proteins Extracellular Signals Can Also Induce Apoptosis Animal Cells Require Extracellular Signals to Survive, Grow, and Divide
CONTROL OF CELL NUMBERS AND CELL SIZE
CONTROL OF CELL NUMBERS AND CELL SIZE Survival Factors Suppress Apoptosis Mitogens Stimulate Cell Division by Promoting Entry into S Phase Growth Factors Stimulate Cells to Grow Some Extracellular Signal Proteins Inhibit Cell Survival, Division, or Growth
Page 634 & 635
Features of Cell Death Ultrastructural by Apoptosis Page 634
Page 636
Page 636
Page 636 & 637
1.Extrinsic apoptotic pathway (the Death Receptor Pathway) 2.Intrinsic apoptotic pathway (the Mitochondrial Pathway) FADD: F as- A ssociated Protein with a D eath D omain Page 636 & 637
Bcl-2 Family Proteins
Bcl-2 Family Proteins Page 636
Page 637 Figure 18–39 Bax and Bak are deathpromoting members of the Bcl2 family of intracellular proteins that can trigger apoptosis by releasing cytochrome c from mitochondria.
Mitochondria-Mediated Apoptosis Page 637
Page 638 Figure 18–40 Activated death receptors initiate an intracellular signaling pathway that leads to apoptosis.
Animal Cells Require Extracellular Signals to Survive, Grow, and Divide The positively acting signal proteins can be classified, on the basis of their function, into three major categories: 1. Survival factors promote cell survival, largely by suppressing apoptosis. 2. Mitogens stimulate cell division, primarily by overcoming the intracellular braking mechanisms that tend to block progression through the cell cycle. 3. Growth factors stimulate cell growth (an increase in cell size and mass) by promoting the synthesis and inhibiting the degradation of proteins and other macromolecule Page 637 & 638
Figure 18–41 Cell death can help adjust the number of developing nerve cells to the number of target cells they contact. If more nerve cells are produced than can be supported by the limited amount of survival factor released by the target cells, some cells will receive insufficient amounts of survival factor to keep their suicide program suppressed and will undergo apoptosis. This strategy of overproduction followed by culling can help ensure that all target cells are contacted by nerve cells and that the “extra” nerve cells are automatically eliminated. Page 639
Figure 18–42 Survival factors often suppress apoptosis by regulating Bcl2 family members. In this case, the survival factor binds to cell-surface receptors that activate an intracellular signaling pathway, which in turn activates a transcription regulator in the cytosol. This protein moves to the nucleus, where it activates the gene encoding Bcl2, a protein that inhibits apoptosis. Page 639
Page 640
Some Extracellular Signal Proteins Inhibit Cell Survival,Division, or Growth Page 641
Apoptosis Depends on an Intracellular Proteolytic Cascade That Is Mediated by Caspases
Apoptosis Depends on an Intracellular Proteolytic Cascade That Is Mediated by Caspases
Fig. 3. Rh4 induces apoptosis in Caco-2 and HCT-116 cells. (A) Hoechst 33,342 staining was used to evaluate cell morphology. Luminous cells are indicative of apoptotic cells. Scale bars = 100 m m. (B) Apoptotic cell ultrastructure was observed under TEM. Scale bars = 1 m m. (C) Apoptosis was analyzed via flow cytometry after Annexin V/PI staining. (D) MMP was assessed with the fluorescent mitochondrial probe JC-10, and the red/green fluorescence intensity was analyzed via flow cytometry. (E) Cells were treated with the indicated concentrations of Rh4 for 24 h, and the levels of apoptosis-related proteins were determined by Western blotting. (F) Western blotting and (G) immunohistochemical staining were performed to analyze the expression level of cleaved caspase 3 in tumor tissues. Values are presented as the means ± SD, n = 3, *p < 0.05, **p < 0.01, ***p < 0.001 compared with the control. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)